While it is understood that depression is an umbrella term for a spectrum of clinical syndromes describing changes in affect, anxiety, psychomotor speed, and cognition, it is not at all clear why some individuals will develop neuropsychiatric impairment while others will not. To better understand the basis for this selective vulnerability, our lab has been investigating the effects of obesity and high fat diet - known risk factors for depression - on neurobehavior in mice. Based on these data we propose the following hypothesis: Selective vulnerability to neuropsychiatric illness is driven by the gut microbiome. This hypothesis is based on the robust and long-lasting effects of modern high fat diets on gut microbiota, producing a gut dysbiosis typified by reduced bacterial diversity and disrupted pathogen/commensal balance. More importantly, we have shown that gut dysbiosis drives neurobehavioral impairment and brain inflammation even in the absence of dietary fat or obesity. These exciting studies demonstrate the clinical significance of the gut-brain axis, and raise the possibility that gut microbiota could be an effective - and accessible - tool to preserve mental health. This concept has raised considerable hope (and hype) in popular literature, but key data are needed to confirm the legitimacy of the microbiome as a valid therapy. First, to ensure that gut dysbiosis is sufficient to disrupt brain function, neurobehavioral impairment must be tied directly to the microbiome without confounds. Secondly, to ensure that gut dysbiosis is necessary for brain dysfunction, rational microbiome-based therapies need to be designed and tested in physiologically relevant models. To meet these needs, we have devised a unique experimental approach (see Fig. 1) that exploits the synergistic interactions of host- and diet-induced drivers of gut dysbiosis, and an adaptive transplantation paradigm that isolates microbiome effects from cofounds introduced by diet, metabolic dysfunction, genetics, and/or obesity. Using this approach, we will map both the pathophysiologic consequences of gut dysbiosis and the therapeutic potential of microbiome manipulation. Specific aim 1 will test if gut dysbiosis caused by high fat/calorie Western diet is sufficient to induce neurobehavioral impairment and brain injury in mice. Aim 2 describes preclinical studies that will test if therapeutic transplantation of gut microbiota can prevent - or reverse - brain injury/dysfunction in the context of Western diet consumption. Completion of these studies will advance understanding of how the microbiome-gut-brain axis participates in mental health. Even more importantly, these studies could identify new approaches that could be quickly translated into safe and effective therapies to preserve mental health.